Antimicrobial peptides are small cationic amphiphilic peptides found in virtually all living organisms (Marr et al., 2006). They play an important role in innate immune defense against various infections (Hancock et al., 2006). In the last decade, there has been significant interest in the development of antimicrobial peptides because of the emergence of antibiotic resistance (Marr et al., 2006; Hancock et al., 2006).
Compared to conventional antibiotics, which target specific metabolic processes in bacteria (Alekshun et al., 2007), antimicrobial peptides are able to form amphipathic structures, where cationic and hydrophobic groups are segregated into two regions, so as to facilitate interaction with the negatively charged bacterial cytoplasmic membrane (Chongsiriwatana et al., 2008). Such interaction is based on the global chemical properties of peptides, rather than their precise sequence (Scott et al., 2008). Therefore, antimicrobial peptides are unlikely to be hindered by the resistance mechanisms observed for current antibiotic treatments (Marr et al., 2006). Furthermore, unlike conventional antibiotics, antimicrobial peptides exhibit broad-spectrum activity against both Gram-positive and Gram-negative bacteria, and even fungi and viruses (Marr et al., 2006; Hancock et al., 2006). They appear to be ideal antibiotic agents to supplement or replace existing treatments (Chongsiriwatana et al., 2008).
However, despite significant enthusiasm, there are intrinsic drawbacks associated with the development of peptide antibiotics due to the peptidic nature of antimicrobial peptides. These include potential immunoreactivity, susceptibility to enzymatic degradation, etc. (Zaiou, 2007). Non-natural peptidomimetic approaches that mimic antimicrobial peptides may circumvent these impediments by introducing amide bond isosteres, and modifying the peptide backbone so as to improve resistance to proteolytic hydrolysis (Violette et al., 2009). To this end, non-natural antimicrobial oligomers, such as 0-peptides, peptoids, arylamides, and oilgourea, have been developed (Tew et al., 2009). However, their rational design sometimes turns out to be complicated due to the difficulty of introducing a variety of functional groups to fine-tune their activity and selectivity, and the inconsistency of their structure-activity-relationship (Fowler et al., 2009). Furthermore, recent research findings from many groups suggest that helical conformations, in which lipophilic and cationic side chains are globally segregated, are not necessary for antimicrobial activity (Schmitt et al., 2007; Mowery et al., 2007). Indeed, a pre-organized secondary structure seems unnecessary for bacterial killing (Scott et al., 2008); instead, oligomers with a strong propensity for helical conformation or conformational rigidity may lead to high hemolytic activity (Chongsiriwatana et al., 2008; Ivankin et al., 2010). Potent antimicrobial activity may actually require the presence of flexible or even random coiled backbones, where side groups are segregated into hydrophobic and cationic regions upon interaction with bacterial membranes (Scott et al., 2008; Ivankin et al., 2010), even if the amphiphilic conformation is irregular and non-helical.
There remains a need for the development of antimicrobial peptide mimetics suitable for the treatment of various microbial diseases. This application discloses a new class of antimicrobial peptide mimetics—γ-AApeptides developed by a simple design strategy. Certain γ-AApeptides were able to disrupt protein-protein interactions (Niu, Hu et al., 2011) and recognize nucleic acids with high affinity and specificity (Niu, Jones et al., 2011), and were highly resistant to protease degradation (Niu, Hu et al., 2011). Moreover, the synthesis and diversification of γ-AApeptides is efficient and straightforward (Niu, Hu et al., 2011), strengthening their potential to generate focused libraries for drug-lead screening. The antimicrobial γ-AApeptides disclosed herein are potent and have broad-spectrum activity, including activity against clinically-relevant strains that are unresponsive to most antibiotics. Also, γ-AApeptides are not prone to select for drug-resistant bacterial strains.